Methylcobalamin vs Cyanocobalamin.pdf

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Chapter
139
Methylcobalamin
versus Cyanocobalamin
Y Bhasker
ABSTRACT
The diagnosis of vitamin B
12
deficiency can now be supported by the
laboratory in view of availability of the facility everywhere to estimate B
12
.
Vitamin B
12
after absorption from the gut is split into two active forms,
methylcobalamin and adenosylcobalamin. The adenosylcobalamin
is an important co-factor in synthesis of neuronal lipids. Rationale in
administration of methylcobalamin alone in B
12
deficiency is critically
analyzed.
Keywords:
Methylcobalamin, methionine synthesis, adenosylcoba-
lamin, methylmalonyl-CoA, succinyl-CoA, neuronal lipids
analogs. These analogs serve no useful function and may compete
with B
12
for serum B
12
binding capacity. The archetypical analog,
cobinamide, is not bound by the primary binding protein specific for
ileal B
12
uptake.
Human body does not synthesize cobalamin. The only source is
food of animal origin—meat, fish and dairy products.
INDIAN SCENARIO
Dietary cobalamin deficiency arises in vegetarians who do not
touch meat, fish, egg and cheese. The largest group in the world
consists of Indian vegetarians.
1,4
Millions of Indian vegetarians are
at risk of cobalamin deficiency on nutritional basis. Subnormal
serum cobalamin levels are found in 50% of randomly selected
young Indian vegetarians, but the deficiency usually does not
progress to megaloblastic anemia since the diet of most vegans
is not totally lacking cobalamin and the enterohepatic circulation
of cobalamin is intact. Dietary cobalamin deficiency may also
arise rarely in nonvegetarian individuals who exist on grossly
inadequate diets because of poverty or psychiatric disturbance.
Daily requirement of vitamin B
12
is 1–3 micrograms. Human
stores are 2–3 milligrams which is sufficient for 2–3 years even if
vitamin B
12
supply is completely cut off.
1
INTRODUCTION
Methylcobalamin was introduced to the medical profession by the
pharma market that methylcobalamin is the active metabolite of
cyanocobalamin.
One can as well prescribe directly the active metabolite in place
of cyanocobalamin, thereby relieving the patient from the burden of
conversion of cyanocobalamin to methylcobalamin and producing
faster, better result, etc.
The logic worked very well and the pharma has uncontrolled
market for methylcobalamin even 15 years after the molecule
introduction. Ironically the basic textbooks of medicine—Davidson’s,
Harrison’s, etc. do not mention methylcobalamin as therapeutic
agent even though three editions have come out ever since the
molecule is available. Not even there is review of the literature on this
molecule in the textbooks, though plenty is available with promoting
agencies.
Encephabal, trental (pentoxifylline) are a few other molecules
promoted earlier, for ischemic strokes, which were never
recommended nor mentioned in the textbooks. These molecules
too had honeymoon days, but disappeared quickly from the market
because of bogus promotion. Whereas methylcobalamin continues
to enjoy supermarket and it is tagged to every other molecule like
pregabalin, statins, antidepressants, so on so forth.
It is most appropriate time to revisit B
12
metabolism and to take a
second look before prescribing methylcobalamin.
ABSORPTION
The ingested cobalamin is released from the dietary protein
complexes by the digestive enzymes, forms cobalamin—intrinsic
factor complex and gets absorbed at the distal ileum.
3,5
Part of it
enters enterohepatic circulation.
1
Some amount of cobalamin is also
derived from the sloughed intestinal cells (some source of vitamin
B
12
for veganins).
The absorbed inert form of cobalamin is converted into two
important active forms.
5,6
One is methylcobalamin—involved in
maturation of red blood corpuscles. The second active form is
adenosylcobalamin involved in healthy myelination and neuronal
integrity.
1,5
Methylcobalamin is the co-factor for methionine syntheses.
Methylation of homocysteine to methionine requires methyl-
cobalamin and five methyl tetrahydrofolate.
1
Briefly, methylcobala-
min enters into folic acid metabolism for formation of methionine
from homocystine which is essential for effective erythropoiesis.
1
Methylcobalamin deficiency leads to folate trap resulting in megalo-
blastic anemia.
The second active form, adenosylcobalamin is the co-factor for the
enzyme methylmalonyl-CoA mutase. It is present in mitochondria.
1
Isomerization of methylmalonyl-CoA to succinyl-CoA (essen-
tial for synthesis of neuronal lipids to form myelin) requires
METABOLISM OF COBALAMIN
Cobalamin or vitamin B
12
is a member of corrin family, known as
hydroxocobalamin in United Kingdom and as cyanocobalamin in the
United States of America.
1
Vitamin B
12
is essential for cellular DNA
synthesis and hence contributes to functions of various tissues of the
body, formation of myelin sheath, more so the rapidly dividing and
proliferating cellular systems such as blood and gastric epithelium.
2,3
Up to 40–50% of serum corrins may be physiologically inactive B
12
Nutrition
adenosylcobalamin.
1,6
Deficiency of adenosylcobalamin leads to
accumulation of large amount of methylmalonyl-CoA resulting
in synthesis and incorporation of nonphysiological fatty acids into
neuronal lipids, causing, demyelination, axonal degeneration and
neuronal death leading to neurological complications.
5,6
In case of
spinal cord damage the values of vitamin B
12
are very low even in the
absence of anemia.
7
From above it is obvious that hematological complications are
due to abnormality in methylcobalamin pathway and neurological
complications are due to abnormality in adenosylcobalamin
pathway.
But, it may be noted, there is no single isolated disease of
methylcobalamin deficiency or isolated disease of adenosylco-
balamin deficiency existing. What existing is the disease due
to cobalamin deficiency, recommending methylcobalamin for
neurological complications of vitamin B
12
deficiency is irrational and
difficult to substantiate?
For cobalamin or vitamin B
12
deficiency only cobalamin is to be
recommended but not methylcobalamin alone.
Section 19
TABLE
2 │ Rarer causes of cobalamin deficiency in India
• Pernicious anemia
9
• Congenital absence or functional abnormality of IF
• Regional enteritis
• Neoplasm
• Selective cobalamin malabsorption
• Fish tapeworm infection
• Transcobalamin II deficiency
• Congenital enzyme defects
icterus. All the above cases received cyanocobalamin only but not
methylcobalamin.
DATA OF A FEW CASES
Vitamin B
12
normal levels in serum—211‒946 pg/ml are mentioned
[interfaced chemiluminescence immunoassay (CLIA)] in
Table 3.
CAUSES OF COBALAMIN DEFICIENCY
The common cause in the western world is lack of intrinsic factor
(IF),
5,6
where as it is a very rare cause in India.
Broadly the two main causes of cobalamin deficiency in India
are—nutrition lacking in vitamin B
12
due to large section of Indian
society adopting vegetarianism, secondly malabsorption due to
various diseases mentioned in
Tables 1 and 2.
COBALAMIN MALABSORPTION IN ELDERLY
Due to inadequate hydrochloric acid and digestive enzymes in the
persons aged above 65 years, the cobalamin bound to meat is not
split effectively.
1,8
Experimentally it is found in these groups when
crystalline cobalamin was administrated orally, the cobalamin
levels measured were normal. Slight elevation of homocystine is an
indicator to suspect vitamin B
12
deficiency in the elderly.
Elderly person needs vitamin B
12
supplementation as there is no
efficient splitting of vitamin B
12
due to impaired digestive functions.
The choice of route of administration is parenteral as most of the
times B
12
deficiency is due to malabsorption and/or nutritional
deficiency.
OUR EXPERIENCE
Out of 28 case studies more than 50% were traditional vegetarians. Six
persons happened to be on vegetarian food even though traditionally
not vegetarians. Two cases were on carbamazepine (anemia) and
two other cases on metformin (anemia and neurological features) for
long time. One case happened to be hyperthyroidism and another
case rheumatoid arthritis (associated autoimmune disorders). Most
of the cases presented with neurological manifestations. Three
cases among vegetarians presented with hemolytic anemia—mild
SUMMARY AND CONCLUSION
Why cobalamin only to be given but not methylcobalamin?
• There is no disease described in human body where conversion
of inactive cobalamin to active methylcobalamin is impaired. So
there is absolutely no necessity to use methylcobalamin in place
of cobalamin.
• There is no isolated disease of methylcobalamin deficiency.
•
Methylcobalamin has little effect on neurological complications
due to vitamin B
12
deficiency.
• When cobalamin deficiency is diagnosed only cobalamin to be
given so that patient gets both methylcobalamin and adenosyl
cobalamin, thereby both hematological and neurological
abnormalities can be corrected simultaneously.
• Finally the costs of cobalamin are less than Rs. 10/- for single
dose whereas methylcobalamin is 510 times more without dual
benefits.
TABLE
1 │ Common causes in India
• Inadequate intake (nutrition)
• Malabsorption
A.
•
•
•
Defective release of cobalamin from food
Gastric achlorhydria
Partial gastrectomy
Drugs blocking acid secretion (PPI)
B. Inadequate production of IF
• Total gastrectomy
C.
•
•
•
Disorders of terminal ileum
Tropical and nontropical sprue
Intestinal resection
Granulomatous diseases
D. Competition for cobalamin
• Bacteria (blind loop syndrome)
E. Drugs
• Colchicines, neomycin, metformin carbamazepine
MESSAGES
• Let us familiarize basics before we go beyond basics.
• Be not the first when the new is tried, nor yet the last to lay the old
aside.
636
Section 19
TABLE
3 │ Case study of vitamin B
12
deficiency
S.
No
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Year of
presentation
May 2002
Jun 1998
Aug 2007
Jun 2009
Jun 1995
Feb 2010
Feb 2007
Jul 1995
Aug 1996
Apr 2010
Jun 2010
May 2010
May 2010
Jun 2010
Dec 2011
Jan 2012
Feb 2012
Aug 2012
Age and sex vegetarian/
nonvegetarian (Veg/NV)
F-34 VEG
F-50 VEG
M-70 VEG
M-40 NV
F-25 NV
F-40 NV
M-20 NV
M-45 NV
F-50 VEG
M-54 VEG
M-31 NV
M-46 VEG
F-44 NV
F-36 VEG
F-20 NV
M-32 VEG
M-60 VEG
M-60 VEG
Chapter 139
Methylcobalamin versus Cyanocobalamin
Presentation
Fatigability, gait ataxia, Romberg’s positive
Polyarthritis—
headache
COPD anemia
Speech disturbance
gait ataxia,
Anemia CHF
Fatigability
Parasthesias of extremities and
hyperpigmentation of knuckles
Anemia, epilepsy, on carbamazepine
Anemia and syncope
A symptomatic (Wife-B
12
Def.)
Easy fatigability, parasthesias of extremities
Gait disturbance
Polyarthralgia
Bil. brachial neuralgia
Seizure disorder
Jaundice, anemia
Parasthesias of extremities
Symmetrical sensory neuropathy
Additional
investigation
-----------------
Anti-CCP negative
RA negative
Hb% 6.2 g
Hb% 8.6 g
Hb% 6.4 g
Hb% 6.4 g macrocytosis,
mega polys
-------------
Hb% 4.6 g macrocytosis
hypersegmented polys
Hb% 6.0 g
Homocysteine-27 µmol/L
------------
-------------
Hyperthyroidism— 10
years
MRI C5C6
Disk degeneration
On carbamazepine 5
years
Indirect
hyperbilirubinemia
DM on metformin
DM on metformin
Vitamin
B
12
levels pg/ml
97
145
92
184
80
Jan-2010
134
190
76-FeB
10
137
125
137
61
85
167
182
96
156
164
Abbreviations:
CCP, Cyclic citrullinated peptide; RA, Rheumatoid arthritis; COPD,
Chronic obstructive pulmonary disease;
Hb,
Hemoglobin;
CHF,
Congestive heart failure; MRI,
Magnetic
resonance imaging; DM, Diabetes mellitus
REFERENCES
1. Kasper DL, Braunwald E, Fauci AS, et al. Harrison’s textbook. Principles
of Internal Medicine, 17th edition. New York: McGraw-Hill Medical
Publishing Division; 2008. chapter 100.
2. Colledge NR, Walker BR, Ralston SH. Davidson’s textbook. Principles
and Practice of Medicine, 21st edition. London: Churchill Livingstone;
2010. pp. 1020-2.
3. Sambulingam K, Sambulingam P. Essentials of Medical Physiology, 5th
edition. New Delhi: Jaypee Brothers Medical Publishers; 2010. p. 73.
4. Khanduri U, Sharma A, Joshi A. occult cobalamin and folate deficiency
in Indians. NatI Med J India. 2005;18:182-3.
5. Satyanarayana U, Chakravarthy U. Textbook of Biochemistry, 3rd
edition. 152-6.
6. Mathew Thomas.
Reappraisal
of megaloblastic anemia in tropics.
Postgraduate Medicine Apicon 2007.
7. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B
12
concentration
in patients without anemia: The effect of folic acid fortification of grain.
Am J Clin Nutr. 2003;77:1474-7.
8. Hershko C, Ronson A, Souroujon M, et al. Variable hematologic
presentation of autoimmune gastritis: Age-related progression from
iron deficiency to cobalamin depletion. Blood. 2006;107: 1673-9.
9. Pruthi RK, Tefferi A. pernicious anemia revisited. Mayo Clin Proc.
1994;69:144-50.
637

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